IBS affects approximately 10-15% or more of the general population. It is the most common disease diagnosed by gastroenterologists and one of the most common disorders seen by primary care physicians. IBS has also been referred to as spastic colon, mucous colitis, spastic colitis, nervous stomach, or irritable colon.
Irritable bowel syndrome is characterized by a group of symptoms in which abdominal pain or discomfort is associated with a change in bowel pattern, such as loose or more frequent bowel movements, diarrhea, and/or constipation.
Irritable bowel syndrome is understood as a multi-faceted disorder. In people with IBS, symptoms result from what appears to be a disturbance in the interaction between the gut or intestines, the brain, and the autonomic nervous system that alters regulation of bowel motility (motor function) or sensory function.
Although the pathophysiology of IBS is incompletely understood, visceral hypersensitivity is thought to have an important role (Holtmann et al. (1997) Am. J. Gastroenterol., 92, 954-959; Trimble et al., (1995) Dig. Dis. Sci., 40, 1607-1613). For example, patients and control subjects were evaluated for their pain thresholds in response to progressive distension of the sigmoid colon induced by a balloon. At the same volume of distension, the patients reported higher pain scores compared to control subjects. This finding has been reproduced in many studies. There are two aspects to visceral hypersensitivity, hyperalgesia and allodynia. Hyperalgesia refers to the situation in which normal visceral sensations are experienced at lower intraluminal volumes. Allodynia refers to the situation where pain or discomfort is experienced at volumes usually producing normal internal sensations (see, for example, Mayer & Gebhart, Basic and Clinical Aspects of Chronic Abdominal Pain, Vol. 9, 1 ed. Amsterdam: Elsevier, 1993:3-28). In animal models, asimadoline has been shown to reduce sensation responses to gastric and colon distention (Burton & Gebhart (1998) J. Pharmacol. Exp. Ther., 285, 707-715), but there is no reason to suspect that asimadoline would selectively benefit one or more subtypes of IBS.
Treatment options for IBS generally include multiple approaches customized to each patient depending upon the severity of the symptoms and the IBS subtype. Patients diagnosed with mild IBS symptoms may be counseled about managing stress and making diet and lifestyle changes. Patients diagnosed with moderate IBS are similarly counseled with the added recommendation of fiber supplements. Depending on the symptoms, moderate IBS patients can also be advised to use antidiarrheals, laxatives, or anticholinergic agents. Typical antidiarrheals include loperamide, attapulgite, and diphenoxylate. Typical laxatives include bisacodyl, senna, polyethylene 3350, and bulk-forming fiber laxatives, such as psyllium, calcium polycarbophil, methylcellulose, and fructan. An example of an anticholinergic used in treating IBS is dicyclomine.
Patients diagnosed with severe IBS may also receive treatment with antidepressants, such as tricyclics and selective serotonin reuptake inhibitors. Severe IBS may also be treated with alosetron or tegaserod.
Alosetron is a 5-HT3 antagonist used for the management of severe IBS-D in women only. It acts on the 5-HT3 receptors of the enteric nervous system of the gastrointestinal tract and is thought to relax the colon and slow the movement of waste through the lower bowel. Notably the drug was removed from the market just nine months after its approval when it was linked to at least four deaths and severe side effects in 197 people. In June 2002, the Food and Drug Administration (FDA) decided to allow alosetron to be sold again with restrictions. The drug can be prescribed only by doctors enrolled in a special program and is intended for severe cases of IBS-D in women who haven't responded to other treatments. It is not approved for use by men.
Tegaserod is a 5-HT4 agonist used for the management of Constipation-predominant IBS (IBS-C) in women. It is a motility stimulant. Therapeutic effect is achieved through activation of 5-HT4 receptors of the enteric nervous system in the gastrointestinal tract. Tegaserod stimulates gastrointestinal motility and the peristaltic reflex, and possibly also reduces abdominal pain. It has been linked to episodes of ischemic colitis. Tegaserod has not been approved for use in men. In 2007, tegaserod was withdrawn from the market due to increased risk of heart attack, stroke and unstable angina in patients taking tegaserod.
IBS patients with an alternating bowel habit pattern present a unique clinical challenge and many of the IBS medications being studied affect either diarrhea or constipation and thus may not be appropriate for IBS-A patients. There is currently no available pharmaceutical treatment for the management of IBS-A.
Thus, there is presently an unmet market need for a safe and efficacious therapeutic agent to treat one or more IBS subtypes in male and female patients.
Here, it has been surprisingly discovered that selective opiate receptor modulators, peripherally selective opiate receptor modulators, peripherally selective kappa-opiate receptor modulators, and peripherally selective kappa-opiate receptor agonists, N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide or pharmacologically acceptable salts thereof can be used for treating diarrhea, or one or more subtypes of IBS, and are particularly useful for the treatment of IBS-D and IBS-A.
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